Process for preparing [S- (R*, S*) ] -beta- [ [ [1- [1-oxo-3- (4-piperidinyl) propyl] -3-piperidinyl] carbonyl]amino] -3-pyridinepropanoic acid and derivatives

ABSTRACT

A process for preparing a compound of formula I  
                 
 
     wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, lower alkyl and halogen

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit to U.S. Provisional ApplicationNo. 60/125,671, filed on Mar. 22, 1999.

BACKGROUND OF THE INVENTION

[0002] Field of the Invention

[0003] The invention relates to a process of preparing[S-(R*,S*)]-β-[[[1-[1-oxo-3-(4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoicacid derivatives represented by the formula

[0004] wherein R¹ and R² are independently selected/from hydrogen, loweralkyl and halogen.

[0005] The compounds of formula I and method of making and using thecompounds of formula I are described in WO 97/41102, Nov. 6, 1997.

[0006] Compounds of formula I are antagonists of the platelet fibrinogenreceptor (GP 11b/111a antagonist). Thus, the compounds of formula I areuseful for the treatment of thrombotic disorders such as restenosispost-angioplasty, unstable/stable angina and myocardial infarction.

[0007] A known method of the preparation of a compound of formula I isdisclosed in WO 97/41102 involving coupling of enantiomerically enrichedmethyl (S)-3-amino-3-pyridylpropanoate withN-(t-butoxycarbonyl)-(R)-nipecotic acid followed by removal of theN-t-butoxycarbonyl protecting group under acidic conditions and couplingwith 3-(N-t-butoxycarbonyl-4-piperidyl)propionic acid. The crude esterproduct is then hydrolyzed using aqueous LiOH and the N-t-butoxycarbonylamino protecting group is removed under acidic conditions withtrifluoroacetic acid (“TFA”). The bis-TFA salt is isolated as a whiteamorphous solid.

[0008] A process for preparing N-(3-piperidinyl carbonyl)-β-alaninederivatives is disclosed in WO 95/08536.

[0009] The current invention relates to a more efficient process ofpreparing compounds of formula I.

BRIEF SUMMARY OF THE INVENTION

[0010] The invention relates to a process of preparing a compound offormula I

[0011] wherein R¹ and R² are independently selected from the groupconsisting of hydrogen, lower alkyl and halogen, comprising coupling3-(N-benzyloxycarbonyl-4-piperidyl)propionic acid calcium salt offormula II as described herein, with (R)-(−)lower alkylnipecotate-(+)-tartrate of formula III, as described herein to form acompound of formula IV

[0012] wherein R³ lower alkyl and Ph is phenyl, reacting the compound offormula IV to form th e compound of formula V

[0013] reacting the compound of formula V with a compound of formula VI

[0014] wherein R¹ and R² are as described above and R⁴ is lower alkyl oraralkyl,

[0015] to form the compound of formula VII

[0016] wherein R¹, R², R⁴ and Ph are as described above, reacting thecompound of formula VII to form the compound of formula VIII

[0017] wherein R¹, R², and Ph are as described above, reacting thecompound of formula VIII to form the compound of formula I.

[0018] In another aspect, the claimed invention relates to a process ofpreparing the compound of formula VI, preferablymethyl(S)-3-amino-3-(3-pyridyl) propanoate, an intermediate in thesynthesis of a compound of formula I, by classical resolution of racemicmethyl 3-amino-3-(3-pyridyl) propanoate using (+)-tartaric acid. Thisnew process led to a more cost effective and volume efficient synthesisof enantiomerically pure methyl (S)-3-amino-3-(3-pyridyl)propanoate ingood yield and high purity.

[0019] Another aspect of the claimed invention relates to a process forpreparing the intermediate (R)-(−)lower alkyl nipecotate (+) tartratesalt which involves resolving racemic (±)lower alkyl nipecotate using(+) tartaric acid in an isopropyl alcohol and water mixture.

[0020] A further aspect of the claimed invention relates to thepurification of the compound of formula I by dissolving the free base offormula I in an organic solvent and adjusting the pH in the range offrom about 4 to about 12 in the presence of an organic amine base toprecipitate the purified compound of formula I.

[0021] Costanzo, et al., in WO97/41102, Nov. 6, 1997 disclose thecompound of formula Ia as a free base. A further aspect of the claimedinvention relates to a novel crystalline form of the compound of formulaIa.

DETAILED DESCRIPTION OF THE INVENTION

[0022] As used herein, the term “alkyl” whether used alone or as part ofa substituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl and the like. Unless otherwisenoted, “lower” when used with alkyl means a carbon chain composition of1-4 carbon atoms. ORT-1593

[0023] As used herein, unless otherwise noted, “aralkyl” shall mean anylower alkyl group substituted with an aryl group such as phenyl,naphthyl and the like.

[0024] The term “halogen” means fluorine, chlorine, iodine or bromine.

[0025] With reference to substituents, the term “independently” meansthat when more than one of such substituents is possible, suchsubstituents may be the same or different from each other.

[0026] The term “hydrogenation catalyst” shall mean a catalyst ofrhodium (Rh), palladium (Pd) or platinum (Pt) which is adsorbed on asolid support such as Rh on carbon, Pd on carbon, Pd(OH) ₂ on carbon orPt on carbon or unsupported such as PtO₂.

[0027] In a preferred embodiment of the invention, the process relatesto a process of preparing a compound of formula I wherein R¹ and R² arehydrogen.

[0028] The invention relates to a process of preparing a compound offormula I as more fully described in the schemes below.

[0029] As set forth in Scheme 1 above, 3-(4-pyridine)acrylic acid, aknown compound, is reduced to 3-(4-piperidyl)propionic acid by catalytichydrogenation in a basic solvent such as inorganic bases, for example,alcoholates, hydroxide, hydrogen carbonate, carbonate of alkali or earthalkali metals or ammonia; or organic bases, for example, primary,secondary, or tertiary alkylamines, in aqueous or alcoholic solution,preferably aqueous ammonia, in the presence of a rhodium catalyst,preferably rhodium on Al₂O₃ at a temperature of from about roomtemperature to about 95°, preferably 80-95° C. at a pH in the range ofabout 7-13, preferably about 7-8.

[0030] 3-(4-Piperidyl)propionic acid is reacted with a reagent capableof placing a benzyloxy carbonyl protecting group on an amine such asN-(benzyloxy carbonyloxy) succinimide (Cb_(z)OSu), N-benzyloxycarbonyloxy-5-norbornene-2,3-dicarboximide, or benzyl chloroformate,preferably benzyl chloroformate in a basic calcium salt, such as aqueousCa(OH) ₂ or calcium carbonate, preferably Ca (OH)₂, at a temperature inthe range of from 0 to room temperature, preferably 0-10° C. andpreferably at a pH in the range of about 8-14, preferably about 11-14,to form the 3-(N-benzyloxycarbonyl-4-piperidyl) propionic acid calciumsalt of formula II.

[0031] The salt of formula II is reacted with (R)-(−)lower alkylnipecotate tartrate of formula III, a known compound or compoundprepared by known methods (J. Org. Chem., 1974, 39(7), 893; Eur., J.Pharmacol., 1983, 89(3-4)217), in the presence of a coupling reagentsuch as 1,3-dicylcohexyl carbodiimide (DCC),O-benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,preferably DCC, in the presence of 0 to 1 equivalents, preferably 0.1equivalents, of an additive such as 1-hydroxybenzotriazole hydrate(HOBT) or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBT),preferably HOBT, in a solvent mixture of an organic solvent and water,such as, ethyl acetate/water or tetrahydrofuran/water or a polar organicsolvent, such as dimethylformamide or 1-methyl-2-pyrrolidinone (NMP), ata temperature in the range of from 0-50° C. preferably 15-25° C. and ata pH in the range of from about 6-10, preferably about 6-7, to form thecorresponding compound of formula IV.

[0032] The compound of formula IV is hydrolyzed in an inorganic basesuch as lithium hydroxide, sodium hydroxide, preferably lithiumhydroxide, in an organic solvent such as THF or dioxane, at atemperature in the range of from about 0 to about 50° C., preferably5-25° C. at a pH preferably in the range of about 10 to about 13, toform the compound of formula V.

[0033] The compound of formula V is reacted with a carboxylic acid saltof the compound of formula VI, preferably the tartrate salt, in thepresence of a coupling reagent such as 1,3-dicyclohexylcarbodiimide(DCC), 0-benzotriazole-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU), or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, preferablyDCC, in the presence of 0 to 1 equivalents, preferably 0.1 equivalentsof an additive such as 1-hydroxybenzotriazole hydrate (HOBT) or3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBT), preferablyHOBT, preferably DCC and HOBT, in the presence of a calcium salt such ascalcium hydroxide, calcium carbonate, and the like, preferably calciumhydroxide, in an amount of at least 1 equivalent, to form thecorresponding compound of formula VII, in a solvent mixture of anorganic solvent and water, such as, ethyl acetate/water ortetrahydrofuran/water or a polar organic solvent, such asdimethylformamide or 1-methyl-2-pyrrolidinone (NMP) at a temperature inthe range of from 0-50° C. preferably 15-25° C. and at a pH in the rangeof from about 6-10, preferably about 6-7.

[0034] Alternatively, the compound of formula V is reacted with acompound of formula VI or an inorganic salt thereof, preferably HClsalt, a known compound or compound prepared by known methods WO97/41102, in the presence of a coupling reagent such as1,3-dicyclohexylcarbodiimide (DCC),0-benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,preferably DCC, in the presence of 0 to 1 equivalents, preferably 0.1equivalents of an additive such as 1-hydroxybenzotriazole hydrate (HOBT)or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBT), preferablyHOBT, preferably DCC and HOBT, to form the corresponding compound offormula VII, in a polar organic solvent such as acetonitrile, DMF, NMP,preferably acetonitrile, in the presence of an organic base such astriethylamine, diisopropylethylamine (DIPEA) or 4-methyl morpholine(NMM), preferably NMM, at a temperature in the range of 0-35° C., and ata pH in the range of about 7-11, preferably in the range of about 8-10.

[0035] The compound of formula VII is reacted in an organic solvent,such as THF, dioxane, or DMF, preferably THF, in the presence of aninorganic base such as sodium hydroxide, or lithium hydroxide,preferably lithium hydroxide, at a temperature in the range of from0-40° C., preferably 10-15° C., preferably at a pH in the range of about8-11. The resulting mixture is acidified with an inorganic acid such assulfuric, hydrochloric, and the like, preferably to a pH of about 3-5,to yield the corresponding compound of formula VIII. When the mixture isacidified with sulfuric acid, the acidification results in theprecipitation of N,N′-bis(2,2,2-trichloro-1-hydroxyethyl)urea (DCU),which is preferably removed prior to the next step.

[0036] The compound of formula VIII is converted to the correspondingcompound of formula I via catalytic hydrogenation using a hydrogenationcatalyst, preferably a palladium catalyst such as Pd/C, in a polarsolvent such as an alcohol, preferably methanol or ethanol, at atemperature of from 30-50° C.

[0037] The compound of formula I is purified by heating the compound offormula I in an organic solvent such as ethylacetate, methyl t-butylether, methanol, ethanol, n-butanol and the like, preferably n-butanol,to a temperature up to 85°, preferably 75-85° C. The solution is thencooled to a temperature in the range of about 20-30° C. An amine organicbase such as triethylamine, cyclohexylamine, t-butylamine and the like,preferably t-butylamine, is added in an amount sufficient to result in apH in the range of about 4-12, preferably about 7-11, most preferably7.5.

[0038] As set forth in Scheme 2 above, a compound of formula IX, a knowncompound or compound prepared by known methods, J. Am. Chem Soc 1957,Vol. 79, p. 159, is converted to a corresponding compound of formula Xby dissolution in an organic solvent such as, methanol, isopropanol,toluene and mixtures thereof, with at least one equivalent of gaseousNH₃ at a temperature in the range of from 40-100° C., preferably 60-65°C. in the presence of a carboxylic acid such as acetic acid or formicacid.

[0039] The compound of formula X is reduced to the correspondingcompound of formula XI, preferably by reacting with borohydride reagentssuch as sodium borohydride, in an organic solvent such as THF, in thepresence of an organic acid such as propionic acid, benzoic acid, aceticacid, or trifluoroacetic acid (TFA), preferably acetic acid or TFA, at atemperature in the range of −5 to 10° C. at a pH in the range of about1-6.

[0040] In the case where the compound of formula X is reduced byreacting with a borohydride reagent, the reaction is quenched with analcohol, preferably methanol and a strong acid such as hydrochloric orsulfuric, preferably hydrochloric, to afford a compound of formula XI asa salt. The amine is freed by reacting the salt of the compound offormula XI with a tertiary amine such as triethylamine, DIPEA, or NMM,preferably triethylamine, in an organic solvent such as acetonitrile,THF, or dioxane, preferably acetonitrile. The resulting tertiary aminesalt is separated by conventional methods such as filtration orextraction, preferably filtration, to afford the compound of formula XIas the free amino ester.

[0041] The compound of formula XI is heated in the presence of(+)-tartaric acid, preferably 0.25 equivalents of (+) tartaric acid, toa temperature resulting in the formation of a solution in a polarsolvent, such as alcohol, for example, methanol or ethanol or an alcoholwater mixture, such as methyl alcohol/water or ethyl alcohol/water,preferably ethyl alcohol/water mixture at a ratio of 90:10 to 100%ethanol, preferably at a ratio of 97:3 and cooled to a temperature inthe range of 25-30° C. to form the corresponding salt of formula XII.

[0042] The tartrate salt of formula XII is converted to thecorresponding compound of formula VI or salt thereof, by known methods.Preferably, the salt of formula XII is reacted with at least twoequivalents, preferably between 8 and 11 equivalents, of gaseous HCl, ina polar solvent, such as methanol, ethanol, isopropyl alcohol, ethylacetate or mixture thereof, at a temperature in the range of 0-50° C.,preferably at about 10° C., to form the corresponding dihydrochloridesalt of formula VI. When R⁴ is methyl, the preferred solvent ismethanol.

[0043] As set forth in Scheme 3 above, the compound of formula XIII, aknown compound or compound prepared by known methods (Eur. J.Pharmacol., 1983, 89(3-4),217), is reacted with (+)tartaric acid,preferably one equivalent (+) tartaric acid in a mixture of isopropylalcohol (IPA) and water, preferably at a ratio of 90:10 up to 100% IPA,more preferably at a ratio of 94:6, and heating to form a solution,preferably at a temperature in the range of from 73-77° C. then cooledto no less than 20° C., preferably 26-30° C., to form the correspondingsalt of formula III.

[0044] A further aspect of the present invention is a novel crystallineforms of the compound of formula Ia, characterized by its x-ray powderdiffraction pattern, utilizing a Philips PW3710 based powderdiffractometer using CuK_(α) radiation and the following systemconditions:

[0045] a) CuKα radiation, 30 mA, 50 KV

[0046] b) Optics

[0047] {fraction (1/12)}° divergence slit

[0048] 0.2 receiving slit

[0049] c) Scan 5.01 to 34.97° 2° at a scan rate of

[0050] 0.020°/1.25 sec 2θ/second

[0051] d) Aluminum sample holder

[0052] The novel crystal form of the compound of formula Ia appears asirregular acicular particles crystals and may be characterizedessentially by its X-ray diffraction pattern: POWDER X-RAY DIFFRACTIONRESULTS d Spacing Relative Angle ° 2θ (Å) Intensity (%)  8.77 10.09 17.50 10.52 8.41 16.20 15.57 5.69 100.00  15.90 5.65 22.70 16.52 5.3748.30 17.48 5.08 25.80 17.72 5.01 24.70 18.32 4.85 58.10 19.62 4.5321.50 19.98 4.45 47.30 20.28 4.38 41.50 21.08 4.22 67.80 21.36 4.1618.10 22.82 3.90 23.50 23.26 3.83 50.40 24.01 3.71 57.60 24.73 3.6024.10 25.62 3.48  9.90 25.99 3.43  8.00 26.37 3.38  4.60 27.37 3.2613.50 27.98 3.19 23.20 28.62 3.12 15.70 30.20 2.96 19.00 30.71 3.4117.30 31.29 2.86 32.40 31.40 2.85 33.30 31.73 2.82 25.10 32.71 2.7412.40 33.84 2.65  9.70 34.55 2.60 10.20

[0053] The following examples describe the invention in greater detailand are intended to illustrate the invention, but not to limit it.

EXAMPLE 1 3-(4-Piperidyl)propionic Acid

[0054] 3-(4-pyridine)acrylic acid (18 kg) was added to 75 kg of water.The resulting suspension was stirred and neutralized (pH 7.5) with 6.8kg of aqueous ammonia (25%). A slurry of Rh/Al₂O₃ (0.9 kg) in 5 kg ofwater was added to the reaction mixture, which was then made inert undernitrogen. The mixture was hydrogenated under a pressure of 3-3.5 bar at85-95° C. After eight hours, when no further change in pressure wasobserved, the mixture was cooled to 25-35° C. The catalyst was filteredand washed 20 with 4.0 kg of water. Ammonia and most of the water in thereaction mixture were removed under vacuum at 80-90° C., and the productbegan to precipitate. Acetonitrile (116 kg) was added and then themixture was concentrated (ca. 50%) under vacuum. Additional acetonitrile(57.1 kg) was added to aid in crystallization and the reaction mixturewas stirred for 1-4 hours at 15-25° C. until precipitation of theproduct was complete. The product was centrifuged and oven dried undervacuum at 45-55° C. to afford 19.1 kg (100%) of the title compound.

EXAMPLE 2 Di 3-(N-Benzyloxycarbonyl-4-piperidyl)propionic Acid CalciumSalt

[0055] 3-(4-Piperidyl)propionic acid (20.0 g, 0.12 mol) and calciumhydroxide (14.1 g, 0.19 mol) were suspended in 47 g water and 195 gacetonitrile at 15-25° C. and then cooled to 0-10° C. Benzylchloroformate (23.9 g, 0.14 mol) was added within 30 minutes and thereaction stirred at 0-5° C. for 2 h. The product precipitated during thereaction and was isolated by filtration to afford the title compound in95% yield.

EXAMPLE 3 (R)-(−)-Ethyl Nipecotate Tartrate

[0056] L-(+)-Tartaric acid (47.74 g, 318 mmol) was suspended in 265 g ofisopropyl alcohol and 16.91 g of water. The mixture was heated to 60-65°C. to afford a homogeneous solution. One equivalent of (±)-ethylnipecotate (50 g, 318 mmol) was added while the temperature wasmaintained at or below 75° C. The mixture was stirred at 70-75° C. for20-30 minutes, then cooled to 60° C. over 60 minutes. Seed crystals of(R)-(−)-ethyl nipecotate -L-(+)-tartrate (25 mg, 0.08 mmol) were addedand the reaction was cooled to 26-30° C. over three hours. Thetemperature was maintained at 26-30° C. for 30 minutes untilprecipitation was complete. The product was isolated (62.0 g, 94.8% de)and washed twice with a mixture of isopropyl alcohol (21.05 g) and water(1.34 g). The crude product was slurried in a mixture of isopropylalcohol (188 g) and water (12 g) at 73-77° C. After stirring for 10-20minutes, the suspension was cooled to 26-30° C. Temperatures exceeding30° C. will result in less yield, while a temperature of less than 25°C. resulted in de <98%. The product was isolated by filtration andwashed twice with a mixture of isopropyl alcohol (21.05 g) and water(1.34 g). This afforded the title compound as a white powder in 72%yield, 98.8% de.

EXAMPLE 4(R)-1-[3-(1-benzyloxycarbonyl-4-piperidyl)-propionyl]-3-piperidinecarboxylicAcid

[0057] 3-(N-Benzyloxycarbonyl-4-piperidyl)propionic acid calcium salt(21.9 g, 32.2 mmol), (R)-ethyl nipecotate (21.7 g, 70.8 mmol), andhydroxy benzyltriazole (HOBT) (1.30 g, 9.65 mmol) were suspended inwater (40 g) and THF (80 g). The resulting suspension was adjusted to pH7 with Ca(OH)₂. Ca-tartrate precipitated and was collected by filtrationand washed with 10 g THF. To the filtrate was added slowly a solution ofDCC (19.9 g, 96.5 mmol) in 40 g of THF at 0-5° C. The reaction mixturewas warmed slowly to 20-25° C. and N,N-dichlorourethane (DCU)precipitated. After 4h, the DCU was removed by filtration and washedwith 8 g of THF. The filtrate was cooled to 0-5° C. and lithiumhydroxide (6.67 g, 159.0 mmol) in 60.38 g of water was added at 0-5° C.The pale yellow solution was warmed to ambient temperature. After 3 h,the solvent was removed by distillation under vacuum at or below 55° C.Ethyl acetate (45.4 g) was added and the pH was adjusted to exactly 4.0with ca. 18.6 g of concentrated HCl. DCU precipitated and was filteredfrom the mixture. The layers were separated and the aqueous layer waswashed twice with 31.8 g of ethyl acetate. The combined organic layerswere washed twice with a solution of 15.8 g NaCl in 47.2 g of water. Theethyl acetate layer was separated and the solvent was removed bydistillation under vacuum at or below 55° C. The product remained as athick pulp. MTBE (70.8 g) was added and the suspension was stirred for30 minutes at 45-50° C., then cooled to 15-25° C. and stirred for onehour until crystallization was complete. The product was centrifuged andwashed with 6.3 g of MTBE, then dried under vacuum at 40-50° C. toafford the title compound in 92% yield and >98% ee.

EXAMPLE 5 Methyl (S)-3-Amino-3-(3-pyridylypropanoate Dihydrochloride

[0058] Two separate procedures were developed to synthesize thiscompound. The first procedure (A) involved two steps for the productionof enantiomerically pure methyl(s)-3-amino-3-(3-pyridyl)propanoatedihydrochloride via NaBH₄ reduction. The second procedure (B) involvedthree steps for the production of enantiomerically puremethyl(S)-3-amino-3-(3-pyridyl)propanoate dihydrochloride viahydrogenation.

[0059] Procedure A:

[0060] Methyl 3-Amino-3-(3-pyridyl)-2-propenoate

[0061] A suspension of methyl nicotinoylacetate dihydrochloride (50.0 g,0.23 mol, dried) and sodium acetate (19.0 g, 0.23 mol) in glacial aceticacid (1.4 g, 0.02 mol), toluene (50 g), and methanol (50 g) was heatedto 60-65° C. Ammonia (14.0 g, 0.82 mol) was bubbled through thesuspension. After four hours, no starting material was present by HPLC.Two-thirds of the solvents were removed by distillation. The solutionwas stirred at 0° C. for one hour, and the precipitate was collected byfiltration and dried to yield 83% of methyl3-amino-3-(3-pyridyl)-2-propenoate. The crude product was used as iswithout further purification.

[0062] Methyl 3-Amino-3-(3-pyridyl)propanoate Dihydrochloride

[0063] Glacial acetic acid (526.9 g, 8.78 mol) was added dropwise at ←5°C. to a suspension of methyl 3-amino-3-(3-pyridyl)-2-propenoate(0.45mol) and sodium borohydride (44.3 g, 1.17mol) in THF (500 g) andthe resulting reaction mixture was stirred at −5-0° C. After 5 h,methanol (600 9) was added dropwise to the solution at -5-0° C. After0.5 hours, HCl (163 g, 4.47 mol) was bubbled through the solution andstirred at 0° C. After 8 h, the white precipitate was filtered off anddried at 40° C. to yield 101.6 g (89%) of methyl3-Amino-3-(3-pyridyl)propanoate dihydrochloride.

[0064] Procedure B:

[0065] Methyl 3-Amino-3-(3-pyridyl)-2-propenoate

[0066] Methyl nicotinoylacetate (88 g, 0.5 mol) was dissolved in toluene(200 g), isopropyl alcohol (200 g), and formic acid (98-100%, 1.22 g,0.03 mol) and heated to 60-65° C. Gaseous ammonia (23 g, 1.35 mol) wasbubbled through the solution for 15 minutes. The white suspension wasstirred at 65° C. until a homogeneous solution formed. The solution wasstirred for two hours at 65° C. and then concentrated (ca. 200 g) at 65°C. The residue was cooled to −5° C. with stirring and methyl3-amino-3-(3-pyridyl)-2-propenoate crystallized as colorless needles.The process of reducing the volume to 50% followed by cooling wasrepeated three times with the mother liquors. Filtration, washing withtoluene, and drying at 30° C. resulted in 77.74 g (88.8%) of methyl3-amino-3-(3-pyridyl)-2-propenoate as colorless crystals.

[0067] Methyl 3-Amino-3-(3-pyridyl)propanoate Dihydrochloride

[0068] Dry palladium on charcoal (0.54 g, manufactured by Degussa, 5%Pd/C) was added to a solution of methyl3-Amino-3-(3-pyridyl)-2-propenoate (5.4 g, 30 mmol) in dry acetic acid(13 g) in a 450 ml Pyrex high-pressure bottle. The reaction mixture washydrogenated at 3-3.2 bar. After 1.5-2 h, the catalyst was filtered andwashed with 20 g of isopropyl alcohol until the wash solvent was nolonger yellow. Gaseous HCl (10.6 g, 0.3 mol) was bubbled through thestirred filtrate at 5-15° C. The suspension was cooled to 0-5° C. andstirred for two hours. The resulting white precipitate was filtered,washed with 5 g of isopropyl alcohol, and dried at 45° C. to yield 5.95g (78.4%,) of methyl 3-Amino-3-(3-pyridyl)propanoate dihydrochloride.

EXAMPLE 6 Methyl (S)-3-amino-3-(3-pyridyl)propanoate Dihydrochloride

[0069] Racemic methyl 3-amino-3-(3-pyridyl)propanoatedihydrochloride(150 g, 0.563 mol) was suspended in acetonitrile (425 g).Triethylamine (125.3 g, 1.239 mol) was added dropwise while thetemperature was maintained at 35° C. or less. The reaction was stirredfor a minimum of two hours at 20° C. then cooled to 50C. After 0.5 hoursthe resulting precipitate was centrifuged and washed with 50 g ofacetonitrile. The acetonitrile was removed by distillation at 40-45° C.to afford crude free base of methyl 3-amino-3-(3-pyridyl)propanoatedihydrochloride. The free base (ca. 105 g) was dissolved in 80 g ofethanol. A solution of (+)-tartaric acid (21.1 g, 0.141 mol) in 80 g ofethanol and 5 g of water was added. The reaction mixture was stirred for4 hours at 20-23° C. The suspension was cooled slowly to 10-15° C., thenstirred for an additional two hours. The precipitate was filtered offand washed with 30 g of ethanol.

[0070] The crude tartrate salt was slurried at 35-40° C. for two hoursin a mixture of 150 g of ethanol and 4.6 g of water. The mixture wasstirred for 0.5 hours at 25° C. The resulting precipitate was isolatedand washed with 30 g of ethanol. Up to three slurries may be necessaryto achieve a >98% de. The precipitate was suspended in methanol (100 g)and a minimum of 10 equiv. HCl gas (51.3 g, 1.408 mol) was added. Thereaction mixture was stirred at 22-28° C. until the reaction wascomplete by HPLC. Ethyl acetate (160 g) was added and the reactionmixture was stirred at 0-5° C. for three hours. The precipitate wasfiltered and washed with 30 g of cold (0-5° C.) methanol. The productwas dried under vacuum at 35-45° C. to yield 39.46 g of the titlecompound as a white solid (28%, 55% of the desired S-enantiomer).

EXAMPLE 7[S-(R*,S*)]-β-[[[1-[1-oxo-3-(4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinePropanoic Acid

[0071](R)-1-[3-(1-benzyloxycarbonyl-4-piperidyl)-propionyl]-3-piperidinecarboxylicacid (60 kg, 149 mol) and HOBT (1.98 kg, 14.8 mol) were suspended inacetonitrile (164 kg) at 0-5° C. NMM (33.2 kg, 328.5 mol) and methyl(S)-3-amino-3-(3-pyridyl)propanoate dihydrochloride (39.2 kg, 154.9 mol)were added to the reaction mixture. After 1 h, a solution of DCC (37.2kg, 180.3 mol) in acetonitrile (117 kg) was added at 0-5° C. The mixturewas warmed to 20-25° C. and stirred for 12 hours. The suspension wascooled to 0-5° C. and the precipitated DCU was filtered off and washedwith 81 kg of pre-cooled ethyl acetate. The solvent was distilled fromthe filtrate, and the residual oil was dissolved twice in 50 kg of ethylacetate and the solvent removed. The resulting oil was dissolved in 162kg of ethyl acetate and washed three times with a solution of 6.3 kg ofNaHCO₃ in 120 kg of water to remove excess HOBT. The solvent was removedfrom the organic layer and the resulting oil and/or foam was dissolvedtwice in 50 kg of THF and evaporated to dryness to afford methyl[S-(R*,S*)-P-[[[1-[1-oxo-3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoate as an oil.

[0072] Crude methyl[S-(R*,S*)-β-[[[1-[1-oxo-3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoate was dissolved in 163 kg of THF at 45° C. The clear solutionwas cooled to 0-5° C. and within 30 to 60 minutes a solution of lithiumhydroxide monohydrate (14.3 kg, 340.8 mol) in 151 kg of water was addedto the reaction mixture. The pale yellow solution was stirred for 2 h at20-25° C. HCl (36-38%, 38 kg) was added to achieve a pH of 4.1. NaCl(7.2 kg) was added and the layers were separated. The organic layer waswashed twice with a solution of 36.4 kg of NaCl in 72.6 kg of water. Theorganic layers were distilled and the resulting oil was dissolved in 75kg of THF. The solvent was removed until a water content of <2% wasachieved. The precipitated inorganic salts were removed and washed with9 kg of THF. The filtrate was evaporated under vacuum at 45° C. toafford[S-(R*,S*)-β-[[[1-[1-oxo-3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoic acid as an oil.

[0073] Crude[S-(R*,S*)-β-[[[1-[1-oxo-3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoic acid was dissolved in 312 kg of methanol. A suspension of 60kg of methanol and 15 kg of slurried Pd/C (wet) was added to thereaction mixture, which was then hydrogenated under pressure (2-3 bar)with stirring at 38-42° C. When the hydrogenation was finished, thecatalyst was filtered through Hyflo SuperCel and washed with 39 kg ofmethanol. The filtrate was reduced to a colorless oil under reducedpressure at 40-50° C. The crude product was dissolved in 60 kg ofn-butyl alcohol and concentrated to an oil, which began to bubble orfoam. The crude product was slurried in 756 kg of n-butyl alcohol andheated to 75-85° C. for 15-20 minutes, then cooled to 20-30° C.t-Butylamine (0.7 kg) was added (pH 7.5) and the reaction was stirred.The reaction mixture was cooled to 0-5° C. and stirred for an additionalhour. The precipitate was isolated, washed with 102 kg of MTBE, anddried under vacuum at 60-80° C. to yield 36 kg (58%) of the titlecompound as a white crystalline solid.

EXAMPLE 8[S-(R*,S*)]-β-[[[1-[1-oxo-3-(4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinePropanoic Acid

[0074](R)-1-[3-(1-benzyloxycarbonyl-4-piperidyl)-propionyl]-3-piperidinecarboxylicacid (1 kg, 2.48 mol), methyl (S)-3-amino-3-(3-pyridyl)propanoatetartrate (where the tartrate is present as a hemi-tartrate) (0.7 kg,2.73 mol) and HOBT (38 g, 0.25 mol) were added to a reaction vessel. Tothe mixture was added a previously prepared cold solution (0-5° C.) ofKH₂PO₄ (96.8 g, 0.71 mol) and Na₂HPO₄ (69.2 g, 0.49 mol) in water (3 kg)and THF (2 kg) The pH was then adjusted to 6.0-6.4 using calciumhydroxide (110 g). The resulting suspension was cooled to 0-5° C. and asolution of DCC (564 g, 2.73 mol) in THF (1 kg) was added. The mixturewas stirred for lh at 0-5° C., warmed to 20-25° C. and stirred for 4 h.The suspension was cooled to 0-5° C. and ethyl acetate (2 kg) was added.After 15 minutes, the precipitate (a mixture of DCU and calciumtartrate) was filtered off and washed with pre-cooled THF (1 kg). Thephases were separated and the organic phase was washed with 5% NaHCO₃ (1kg). The organic phase was concentrated at 40-50° C., the residual oilwas dissolved in THF (1 kg) and evaporated to dryness to afford methyl[S-(R*,S*)-β-[[[1-[1-oxo-3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoate as an oil.

[0075] Crude methyl[S-(R*,S*)-β-[[[1-[1-oxo-3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoate was dissolved in THF (1.4 kg) at 45° C. The clear solutionwas cooled to 0-5° C. Within 30-90 min, a solution of lithium hydroxidemonohydrate (182 g, 4.21 mol) in water (1.9 kg), cooled to 5° C., wasadded to the reaction mixture. The solution was stirred for 0.5 h at0-5° C., warmed to 20-25° C. and stirred for an additional 1 h. Thereaction mixture was cooled to 0-5° C. and treated with a solution ofsulfuric acid (250 g) in water (1.14 kg) to achieve a pH of 3.9-4.1. Theprecipitated DCU was collected by filtration and washed with THF (400g). The resulting phases were separated and the organic phase washedwith a saturated NaCl solution (1 kg). The organic layer was distilledand the resulting oil dissolved in THF (2 kg). The solvent was removeduntil a water content of <2% was achieved. The precipitated inorganicsalts were removed. The filtrate was concentrated and the resulting oildissolved in MeOH (2kg). The solution was evaporated under vacuum at 45°C. to afford[S-(R*,S*)-β-[[[1-[1-oxo-3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoic acid as an oil.

[0076] Crude[S-(R*,S*)-β-[[[1-[1-oxo-3-(1-benzyloxycarbonyl-4-piperidinyl)propyl]-3-piperidinyl]carbonyl]amino]-3-pyridinepropanoic acid was dissolved in a suspension of Pd/C (261 g) in MeOH (3kg). The reaction mixture was hydrogenated under pressure (2-3 bar) withstirring at 30-40° C. After 6 h, the catalyst was filtered through HyfloSuperCel and washed with methanol (1.04 kg). The filtrate wasconcentrated under reduced pressure at 40-50° C. The crude product wasdissolved in n-butyl alcohol (1 kg) and concentrated to an oil. Thecrude product was taken up in n-butyl alcohol (1.7 kg) and heated to75-85° C. for 1-3 h, then cooled to 20-30° C. for 2-3 h. The resultingsuspension was cooled to 0-5° C. and stirred for an additional 1 h. Theprecipitate was isolated, washed with MTBE (1.7 kg), and dried undervacuum at 60-80° C. to yield 36 kg (53%) of the title compound as awhite crystalline solid.

1. A process for preparing a compound of formula I

wherein R¹ and R² are independently selected from the group consistingof hydrogen, lower alkyl and halogen, comprising reacting the salt offormula II

with the salt of formula III

at a pH in the range of about 6 to 10 to form the compound of formula IV

reacting the compound of formula IV to form the compound of formula V

reacting the compound of formula V with a compound of formula VI

at a pH in the range of about 7 to 11 to form the compound of formulaVII

reacting the compound of formula VII to form the compound of formulaVIII

and reacting the compound of formula VIII with hydrogen in the presenceof a hydrogenation catalyst to form the compound of formula I.
 2. Theprocess of claim 1, wherein in the compound of formula I R¹ and R² arehydrogen.
 3. A process for preparing a compound of formula VI

wherein R¹ and R² are independently selected from hydrogen, lower alkyland halogen, and R⁴ is lower alkyl or aralkyl, or salt thereofcomprising reacting a compound of formula XI

with (+)tartaric acid to form the salt of formula XII

and reacting the salt of formula XII to form the compound of formula VIor salt thereof.
 4. The process of claim 3, wherein in the compound offormula XI R⁴ is methyl and the (+)tartaric acid is present in an amountof 0.25 equivalents.
 5. The process of claim 4, wherein in the compoundof formula VI, R¹ and R² are hydrogen and R⁴ is methyl.
 6. The processof claim 4, wherein the salt of formula XII is reacted with gaseous HClin methanol to form the dihydrochloride salt of formula VI.
 7. A processof preparing a salt of formula III

wherein R³ is lower alkyl comprising reacting a compound of formula XIII

with (+)tartaric acid in a mixture of isopropyl alcohol and water. 8.The process of claim 7, wherein in the salt of formula III, R³ is ethyl.9. The process of claim 8, wherein in the mixture of isopropyl alcoholand water the isopropyl alcohol is present in a ratio of from 90 percentisopropyl alcohol to 10 percent water to 100 percent isopropyl alcohol.10. A process of purifying a compound of formula I

wherein R¹ and R² are independently selected from the group consistingof hydrogen, lower alkyl and halogen, comprising reacting the free baseof formula I at a pH in the range of from about 4 to 12 in the presenceof an organic amine base.
 11. The process of claim 10, wherein in thecompound of formula I R¹ and R² are hydrogen.
 12. The process of claim11, wherein the organic amine base is triethylamine, cyclohexylamine, ort-butylamine and the reaction is carried out at a pH in the range offrom about 7 to
 11. 13. The process of claim 12, wherein the reaction iscarried out at a pH of 7.5.
 14. The process of claim 13, wherein theorganic amine base is t-butylamine.
 15. A process for preparing acompound of formula VIII

wherein R¹ and R² are independently selected from the group consistingof hydrogen, lower alkyl and halogen, comprising reacting a compound offormula V

wherein Ph is phenyl, with a carboxylic acid salt of a compound offormula VI

wherein R¹ and R² are independently selected from the group consistingof hydrogen, lower alkyl and halogen, and R⁴ is lower alkyl or aralkyl,in the presence of a calcium salt, in an amount equal to at least 1equivalents, at a pH in the range of about 6-10.
 16. The process ofclaim 15, wherein the carboxylic acid salt of the compound of formula VIis tartrate salt.
 17. The process of claim 15, wherein the calcium saltis calcium hydroxide.
 18. The process of claim 15, wherein the pH is inthe range of about 6-7.
 19. A crystalline form of the compound offormula Ia

characterized essentially by the following X-ray diffraction pattern: dSpacing Relative Angle ° 2θ (Å) Intensity (%)  8.77 10.09  17.50 10.528.41 16.20 15.57 5.69 100.00  15.90 5.65 22.70 16.52 5.37 48.30 17.485.08 25.80 17.72 5.01 24.70 18.32 4.85 58.10 19.62 4.53 21.50 19.98 4.4547.30 20.28 4.38 41.50 21.08 4.22 67.80 21.36 4.16 18.10 22.82 3.9023.50 23.26 3.83 50.40 24.01 3.71 57.60 24.73 3.60 24.10 25.62 3.48 9.90 25.99 3.43  8.00 26.37 3.38  4.60 27.37 3.26 13.50 27.98 3.1923.20 28.62 3.12 15.70 30.20 2.96 19.00 30.71 3.41 17.30 31.29 2.8632.40 31.40 2.85 33.30 31.73 2.82 25.10 32.71 2.74 12.40 33.84 2.65 9.70 34.55 2.60 10.20